TRPA1 (ANKTM1, p120) is a non-selective cation channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified as a transformation sensitive mRNA in cultured human lung fibroblasts (Jaquemar et al., J. Bio. Chem., 1999, 274, 7325-7333). Subsequent studies indicated that TRPA1 is also highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia as well as in hair cells of the inner ear (Story et al., Cell, 2003, 112, 819-829; Corey et al., Nature, 2004, 432, 23730; Nagata et al., J Neurosci., 2005, 25, 4052-4061; Diogenes et al., J. Dent. Res., 2007, 86, 550-555). In sensory neurons, TRPA1 expression is most abundant in small diameter neurons where it co-localizes with markers of peptidergic nociceptors such as TRPV1, CGRP and substance P (Story et al., supra; Bautista et al., PNAS, 2005, 102, 12248-12252; Nagata et al., J. Neurosci., 2005, 25, 4052-4061; Diogenes et al., J. Dent. Res., 2007, 86, 550-555).
The finding that TRPA1 is expressed in small diameter nociceptors has led to the suggestion that this channel may be involved in pain sensation. Indeed a number of additional observations support this suggestion. For example, TRPA1 expression is increased by inflammatory mediators such as NGF (Diogenes et al., J. Dent. Res., 2007, 86, 550-555) and following nerve injury or inflammation (Obata et al., J. Clin. Invest. 2005, 115, 2393-2401; Frederick et al., Biochem. Biophys. Res. Commun., 2007, 358, 1058-1064). Bradykinin, a potent algogenic peptide released at sites of injury and inflammation, activates TRPA1 via G-protein coupled BK2 receptors (Bandell et al., Neuron, 2004, 41, 849-857). In addition, TRPA1 is activated by a range of pungent or irritant compounds per se eliciting pain in animals and humans, such as mustard oil (AITC), cinnamaldehyde, acreolin, allicin, and formalin (Bandell et al., supra; Namer et al., Neuroreport, 2005, 16, 955-959; Bautista et al., Cell, 2006, 124, 1269-1282; Fujita et al., Br. J. Pharmacol., 2007, 151, 153-160; McNamara et al., PNAS, 2007, 104, 13525-13530).
Finally, TRPA1 may also be activated by noxious cold (Bandell et al., Neuron, 2004, 41, 849-857; Jordt et al., Nature, 2004, 427, 260-265; Nagata et al., J. Neurosci., 2005, 25, 4052-4061) and the intra-thecal administration of TRPA1 anti-sense oligodeoxynucleotide suppresses inflammation as well as nerve injury, induced cold allodynia (Obata et al., J. Clin. Invest., 2005, 115, 2393-2401). Likewise, mustard oil and bradykinin-induced acute pain and hyperalgesia is abolished in TRPA1−/− mice (Bautista et al., supra; Kwan et al., Neuron, 2006, 50, 277-289).
TRPA1 receptors also play a role in airway disorders. Treatment with cigarette smoke extracts (CSE) increases Ca2+ influx in TRPA1-transfected cells, and promotes neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE on Ca2+ influx in dorsal root ganglion neurons is abolished in TRPA1-deficient mice. These data suggest a role for TRPA1 in the pathogenesis of CSE-induced diseases such as chronic obstructive pulmonary disease (COPD) (Andre et al., J. Clin. Invest., 2008, 118, 2574-2582).
Recent data highlighted the TRPA1 channel role in inflammation and bronchial hypereactivity in a murine asthma model. Other studies provided evidence that inhalation of TRPA1 stimulants elicited cough reflex in guinea pigs and human volunteers. (Facchinetti et Patacchini, The Open Drug Discovery J. 2010, 2, 71-80). TRPA1 antagonists could emerge as novel drugs for treatment of COPD, asthma and chronic cough.
TRPA1 is found also in bladder and urethra urothelium, epithelium and nerve fibers of the urothelium, sub-urothelial space, muscle layers and around blood vessels (Du et al., Urology, 2008, 72, 450-455; Andrade et al., Biochem. Pharmacol., 2006, 72, 104-114; Gratzke et al., Eur. Urology, 2008, Apr. 30 e-pub; Streng et al., Eur. Urology, 2008, 53, 391-400). TRPA1 expression is increased in bladder mucosa from patients with bladder outlet obstruction (Du et al., Urology, 2008, 72, 450-455). Activation of TRPA1 increases micturition frequency and reduces voiding volume (Streng et al., supra).
Activation of TRPA1 in the bladder by reactive metabolites of cyclophosphamide (e.g., acrolein) may be responsible for cystitis that sometimes accompanies the use of chemotherapeutic agents (Bautista et al., supra). TRPA1 is also expressed in colonic afferents, is upregulated following induction of experimental colitis, and TRPA1 antisense oligonucleotides suppresses colitis-induced hyperalgesia to colonic distension (Yang et al., Neurosci Lett., 2008, 440, 237-241). These data suggest a role for TRPA1 in the pathogenesis of visceral pain and dysfunction, such as bladder instability, urinary incontinence, cystitis and colitis.